Alzheimer's disease (AD) is a progressive disease resulting in senile dementia. See generally Selkoe, TINS 16, 403-409 (1993); Hardy et al., WO 92/13069; Selkoe, J. Neuropathol. Exp. Neurol. 53, 438-447 (1994); Duff et al., Nature 373, 476-477 (1995); Games et al., Nature 373, 523 (1995). Broadly speaking, the disease falls into two categories: late onset, which occurs in old age (65+ years) and early onset, which develops well before the senile period, i.e., between 35 and 60 years. In both types of disease, the pathology is the same but the abnormalities tend to be more severe and widespread in cases beginning at an earlier age. The disease is characterized by at least two types of lesions in the brain, senile plaques and neurofibrillary tangles. Senile plaques are areas of disorganized neuropil up to 150 μm across with extracellular amyloid deposits at the center visible by microscopic analysis of sections of brain tissue. Neurofibrillary tangles are intracellular deposits of microtubule associated tau protein consisting of two filaments twisted about each other in pairs.
The principal constituent of the plaques is a peptide termed Aβ or β-amyloid peptide. Aβ peptide is an internal fragment of 39-43 amino acids of a precursor protein termed amyloid precursor protein (APP). Several mutations within the APP protein have been correlated with the presence of Alzheimer's disease. See, e.g., Goate et al., Nature 349, 704) (1991) (valine717 to isoleucine); Chartier Harlin et al. Nature 353, 844 (1991)) (valine717 to glycine); Murrell et al., Science 254, 97 (1991) (valine717 to phenylalanine); Mullan et al., Nature Genet. 1, 345 (1992) (a double mutation changing lysine595-methionine596 to asparagine595-leucine596). Such mutations are thought to cause Alzheimer's disease by increased or altered processing of APP to Aβ, particularly processing of APP to increased amounts of the long form of Aβ (i.e., Aβ1-42 and Aβ1-43). Mutations in other genes, such as the presenilin genes, PS1 and PS2, are thought indirectly to affect processing of APP to generate increased amounts of long form Aβ (see Hardy, TINS 20, 154 (1997)).
The pathogenic role of the amyloid peptide aggregated into plaques has been known for many years. However, severity of dementia is weakly correlated with the density of plaques, whereas a significant correlation exists with the levels of soluble Aβ (McLean et al., Ann. Neurol. 1999, 46:860-866). Recent studies have suggested that Aβ oligomers are implicated in synaptotoxicity and memory impairment in hAPP transgenic mice (Mucke et al., J Neurosci. 20:4050-4058 (2000); Morgan et al., Nature 408:982-985 (2000), Dodart et al., Nat Neurosci, 5:452-457 (2002). Aβ oligomers, but not monomers or fibrils, also inhibit hippocampal long-term potentiation (Walsh et al., Nature 416:535-539 (2002). The primary structure of the neurotoxic species of the “Aβ oligomer” is an area of active investigation. It has been suggested that the neurotoxic species is an oligomer of the Aβ peptides that begin at position 2 of Aβ (the alanine following the asparagines) (Podlisny, M., et al. JBC (1995) 270: 9564-9570.